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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be in range of  350 mg/kg bw/day for F0, F1 generation. When male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on reproductive toxicity studies on rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
other: 1.Charles River 2.Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
No data available
Details on mating procedure:
- M/F ratio per cage: 20: 20
- Length of cohabitation: 17 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1
Exposure period: 2 years
Premating exposure period: male: 84 days, female: 84 days
Duration of the test: 3 generations
Study 2.
90 days
Frequency of treatment:
continuous in feed
Details on study schedule:
The first litters of each generation (Fla- and F2a-generation) were sacrificed at 21 days of age. Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation. From the Flb-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies. Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old, and were continued until the F3b generation was weaned.
Remarks:
Study1
0.0,14.0,70.0,350.0mg/kg bw
Study2.
0.0,8.8,44,220 mg/kg bw
No. of animals per sex per dose:
Study1
Total:400
0 mg/kg bw d (control): 50 males and 50 females
14 mg/kg bw d: 50 males and 50 females
70 mg/kg bw d: 50 males and 50 females
350 mg/kg bw d: 50 males and 50 females
Study 2.
Total:80
0.0 mg/kg bw/day :10 males and 10 females
8.8 mg/kg bw/day :10 males and 10 females
44.0 mg/kg bw/day :10 males and 10 females
220.0 mg/kg bw/day :10 males and 10 females
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OTHER:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.: No data

Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
GROSS NECROPSY: Yes


Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Statistics:
No data available
Reproductive indices:
All reproductive parameters, including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth were measured.
Offspring viability indices:
No data available
Clinical signs:
no effects observed
Description (incidence and severity):
2.No abnormal reactions were noted.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two males at the 0.02% dietary level died in the early stages of the study. These deaths were attributed to respiratory illness, not to ingestion of the test material.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No statistically significant effects for treatments were disclosed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Findings of test and control groups were comparable.No abnormalities resulted from ingestion of the test substance.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No definitive adverse effects due to the test material were noted in the haematology and pathology.
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Description (incidence and severity):
The results of urine analyses revealed no significant differences between test animals and control animals respecting the presence of reducing substances, protein, and microscopic elements.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No adverse effects were observed on histopathology.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
General reproduction including fertility gestation, parturition, neonatal viability, lactation, and post-weaning growth was normal for all test groups and did not deviate from the controls in each generation.
General reproduction including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth was normal for all test groups and did not deviate from the controls in each generation. No gross abnormalities were noted. No definitive adverse effects due to the test material were noted in the haematology and pathology.
Dose descriptor:
NOAEL
Effect level:
>= 220 - <= 350 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
gross pathology
reproductive performance
other: No effects were noted.
Remarks on result:
other: No effects on reproductive performance
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No definitive adverse effects due to the test material were noted in the haematology and pathology.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross abnormalities were noted.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
General reproduction including fertility gestation, parturition, neonatal viability, lactation, and post-weaning growth was normal for all test groups and did not deviate from the controls in each generation.
General reproduction including fertility gestation, parturition, neonatal viability, lactation, and post-weaning growth was normal for all test groups and did not deviate from the controls in each generation. No gross abnormalities were noted. No definitive adverse effects due to the test material were noted in the haematology and pathology.
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
gross pathology
reproductive performance
other: No effects were noted.
Remarks on result:
other: No effects on reproductive performance
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
General reproduction including neonatal viability and post-weaning growth was normal for all test groups and did not deviate from the controls.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
350 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No definitive adverse effects due to the test material were noted.
Remarks on result:
other: No effects on developmental parameters
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
General reproduction including neonatal viability and post-weaning growth was normal for all test groups and did not deviate from the controls.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
350 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No definitive adverse effects due to the test material were noted.
Remarks on result:
other: No effects on developmental parameters was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Under the condition of the study, the reproductive NOAEL for test substance was considered to be 350 mg/kg bw/day.
Executive summary:

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 1

In a three generation reproduction study, rats were given the test substance in the diet for approximately 2 years (Buehler et al. 1971). Four groups of male and female weanling rats received dietary doses equivalent to 14, 70 and 350 mg/kg bw d, with 50 animals of each sex per dose group. All reproductive parameters, including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth were normal for all test groups. In addition, no definitive adverse effects in hematology and pathology or gross abnormalities were noted.

Therefore, the reproductive NOAEL is 350 mg/kg bw/day.

NOAEL Parental: = 0.5%. (350 mg/kg bw d)

NOAEL F1 Offspring: = 0.5% (350 mg/kg bw d)

NOAEL F2 Offspring: = 0.5% (350 mg/kg bw d)

Study2

The reproductive toxicity study of test material in rats was conducted to evaluate the adverse effects by oral route. Test material was fed to rats at dietary levels of 0.02%, 0.1%, and 0.5% (equivalent to 8.8, 44, 220 mg/kg bw/day ) for 90 days. No adverse effects were found upon the following parameters: growth, food consumption, food utilization, survival, hematologic values, urinary analytical values, organ weights, and organ:body weight ratios. There were no gross or microscopic tissue changes attributable to ingestion of the test material. Therefore, no adverse effects (NOAEL) were observed in a 90-day oral feed study in rats at doses as high as 220 mg/kg bw/day (highest dose tested).

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 350 mg/kg body weight/day,when male and female rats were treated with test material orally,Thus, comparing this value with the criteria ofCLP regulationtest materialis not likely to classify as reproductive toxicant.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 1

In a three generation reproduction study, rats were given the test substance in the diet for approximately 2 years (Buehler et al. 1971). Four groups of male and female weanling rats received dietary doses equivalent to 14, 70 and 350 mg/kg bw d, with 50 animals of each sex per dose group. All reproductive parameters, including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth were normal for all test groups. In addition, no definitive adverse effects in hematology and pathology or gross abnormalities were noted.

Therefore, the reproductive NOAEL is 350 mg/kg bw/day.

NOAEL Parental: = 0.5%. (350 mg/kg bw d)

NOAEL F1 Offspring: = 0.5% (350 mg/kg bw d)

NOAEL F2 Offspring: = 0.5% (350 mg/kg bw d)

Study2

The reproductive toxicity study of test material in rats was conducted to evaluate the adverse effects by oral route. Test material was fed to rats at dietary levels of 0.02%, 0.1%, and 0.5% (equivalent to 8.8, 44, 220 mg/kg bw/day ) for 90 days. No adverse effects were found upon the following parameters: growth, food consumption, food utilization, survival, hematologic values, urinary analytical values, organ weights, and organ:body weight ratios. There were no gross or microscopic tissue changes attributable to ingestion of the test material. Therefore, no adverse effects (NOAEL) were observed in a 90-day oral feed study in rats at doses as high as 220 mg/kg bw/day (highest dose tested).

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 350 mg/kg body weight/day,when male and female rats were treated with test material orally,Thus, comparing this value with the criteria ofCLP regulationtest materialis not likely to classify as reproductive toxicant.

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Additional information